An investigation into neurotoxic mechanisms in haloperiod-induced tardive dyskinesia

Abstract:

A delicate balance exists between nitric oxide mediated neuroprotective and neurotoxic actions. Under physiological conditions nitric oxide reacts with various reactive species, such as superoxide, peroxide, peroxynitrite and lipid peroxyl radicals, suggesting a protective role against oxidative stress. However, excessive nitric oxide production is associated with the inhibition of key enzymes important for energy metabolism, while it can also mediate DNA damage, and provoke the generation of reactive oxygen species. Thus, excessive nitric oxide has been implicated in neurodegenerative diseases as well as schizophrenia and affective illnesses. Haloperidol, although one of the most widely prescribed antipsychotic drugs, causes numerous side effects with the most troublesome being extrapyramidal symptoms. One such side effect, namely tardive dyskinesia, is a potentially irreversible syndrome, which develops relatively late in the course of drug treatment and worsens after acute withdrawal of the drug. Several neurotoxic mechanisms have been proposed to mediate chronic haloperidol-induced tardive dyskinesia and include the ability of this antipsychotic drug, and/or its various metabolites, to alter neurotransmission, generate free radicals and to inhibit nitric oxide synthesis. Thus, considering the dual nature of nitric oxide, it can either exacerbate haloperidol-induced neurotoxicity and ultimately cause a neurodegenerative disorder, or it can reverse or inhibit the neurotoxic mechanism causing tardive dyskinesia. In order to investigate the role of nitric oxide in haloperidol, and in haloperidol withdrawal associated extrapyramidal symptoms and tardive dyskinesia, a rat model of extrapyramidal symptoms and tardive dyskinesia was developed. In the present study, two haloperidol treatment protocols were analysed. Saline, haloperidol, the nitric oxidecyclic guanosine monophosphate modulator, methylene blue and a combination of haloperidol and methylene blue, were administrered in a sub-acute as well as a long-term haloperidol treatment protocol. All oral-buccal movements of the different treatment groups were studied at regular time intervals throughout the two treatment protocols. At the termination of the haloperidol treatment and withdrawal period, striatal cyclic guanosine monophosphate and serum nitrogen oxides were determined at sacrifice using a radiometric assay for cyclic guanosine monophosphate determination and a cadmium-based reduction assay for serum nitrogen oxides. In the long-term protocol, haloperidol was administrated for seventeen weeks, followed by an acute withdrawal of the drug for three weeks. In addition, two chronic treatment protocols were used to assess the interference of early disruption of the nitric oxidecyclic guanosine monophosphate pathway as well as of late disruption of this transduction pathway immediately prior to haloperidol withdrawal. The resulting effects on nitric oxide and cyclic guanosine monophosphate, as well as behaviour were then determined. In these latter sub-groups, methylene blue was administered either from week 1-3 of the chronic haloperidol treatment protocol, or from week 14-17. Finally, in order to access the effects of haloperidol and methylene blue on the above mentioned parameters during short-term administration, both drugs were administered separately, as well as together, over a sub-acute treatment period of 3 weeks. These data were related to those occurring during and after the chronic treatment protocols. After the selected treatment periods, abnormal oral movements were used to measure extrapyramidal symptoms and were compared to peripheral (nitrogen oxides) and central markers (cyclic guanosine monophosphate) of the nitric oxide-cyclic guanosine monophosphate transduction pathway. This would effectively asses a possible role for nitric oxide in the mechanisms of haloperidol induced extrapyramidal symptoms, as well as in acute haloperidol withdrawal related motor and biochemical changes. Chronic haloperidol, followed by acute withdrawal, induced a significant suppression of both serum nitrogen oxides as well as striatal cyclic guanosine monophosphate. These parameters were also found to be further attenuated by both early and late manipulation with methylene blue, with greater inhibitory effects observed with regards to striatal cyclic guanosine monophosphate. Early administration of methylene blue engendered the most profound striatal cyclic guanosine monophosphate suppression. Behavioural analysis of vacuous chewing movements reflects that, although the treatment period and withdrawal periods were possibly too short, there was strong evidence that blocking cyclic guanosine monophosphate with methylene blue exacerbates haloperidol-associated vacuous chewing movements and also worsens that after acute haloperidol withdrawal. During sub-acute haloperidol treatment, no nitrogen oxide changes were observed, although combining haloperidol with methylene blue induced a significant decrease in cyclic guanosine monophosphate. Sub-acute haloperidol induced significant extrapyramidal symptoms over the 3 week treatment period. Although methylene blue induced no increase in vacuous chewing movements, it significantly amplified halperidol-induced vacuous chewing movements, directly implicating a cyclic guanosine monophosphate mediated mechanism in haloperidol-associated vacuous chewing movements. The results of this in vivo study suggest that long-term haloperidol is associated with extrapyramidal symptoms which are closely linked to its ability to modulate the striatal nitric oxide-cyclic guanosine monophosphate pathways, and that withdrawal of the drug exacerbates this response. Furthermore, exacerbation of haloperidol action with methylene blue implicates nitric oxide in a neuroprotective function in haloperidol-induced neurological dysfunction. Finally, this study provides the first supportive evidence for the use of serum nitrogen oxides as a potentially useful non-invasive peripheral marker of brain nitric oxide activity.